Rheumatoid factors are 9s IgM autoantibodies directed against the
hinge regions of 7s IgG's that have been changed consequent to
their encounter with a foreign antigen, such as those produced by oral
bacteria. Occasionally self-aggregating 7 s IgG's serve this
function. When these complexes are taken up by phagocytes in the joint,
they form the "RA cell," a cell analogous to the LE cell of
Hargraves. The circulating complexes, which activate complement cascades
in the joint, are not specific for RA, being found in other rheumatic
and autoimmune diseases as well as having a low prevalence in the normal
population. Recently, other antigens resulting in autoimmune complex
formation with greater specificity for RA have been described. These
antibodies, known as anti-cyclic citrullinated peptide (anti-CCP)
antibodies recognize citrullinated protein residues, which are present
as antigenic determinants in patients with RA. This is in contrast to
systemic lupus erythematosus (SLE), another autoimmune disease
characterized by immune complexes in the systemic circulation. In the
case of SLE, 7s IgG's directed against several nuclear antigens
localize mainly in the kidneys and blood vessels. They also produce
cerebral and pulmonary disease by activating complement systemically.
Genetic defects in the complement cascade associated with SLE result in
inadequate clearance of immune complexes as well as apoptotic blebs
containing autoantigens.

Rheumatology came late to the game of medical science and even
later to immunology. From 1933 to 1948, our medical specialty was a
descriptive art-we had no idea, in any meaningful way, what was going
on. Cardiologists had their EKGs and digitalis, the endocrinologists had
their thyroid tests and extracts, but rheumatologists seemed condemned
to stand idly by to watch their patients turn into cripples or die in
lupus crisis after one or another stopgap treatments. Oh yes, we had
diathermy, gold salts, paraffin injections and, believe it or not, bee
venom. We knew how to treat gout with colchicine, were just learning to
give penicillin to prevent rheumatic fever, but by and large our
treatment of joint disease or even systemic lupus erythematosus (SLE)
was limited to aspirin, aspirin, and more aspirin. All that changed in
the annus mirabilis of our field, 1948.

At a staff meeting of the Mayo Clinic in January of 1948, Malcolm
M. Hargraves described a strange kind of cell that formed in blood
samples of patients with SLE.1 Before 1950, we could not really tell who
had SLE and who did not; we had "no clue" as to why SLE was so
often fatal. Hargraves had discovered what he called the "LE
cell," which finally permitted us not only to make a diagnosis of
the disease, but also told us what was going wrong with these poor
women. The LE cell, it turned out over the years, is a white blood cell
(a neutrophil) that has ingested the dying nucleus of another cell,
against which lupus patients make antibodies. Complement was involved,
acting as an opsonin. It also turned out that those antibodies against
the nucleus and/or its constituents--the anti-DNA antibodies--were just
the tip of an iceberg. SLE patients produce a dazzling number of
antibodies, with their Fab regions directed against bits and pieces of
their own cells. Their immune system recognizes such bits of
"self" as if they were a microbe, a tad of "non-self that
wants expunging. Hargrave's discovery of the LE cell sparked the
study of autoimmunity and lifted rheumatology over the threshold of
science. (1)

In the same month, immunologist Harry Rose and rheumatologist
Charles Ragan of Columbia described a factor in the serum of most
patients with rheumatoid arthritis (RA) that clumped sheep red blood
cells coated with human antibodies: the "sensitized sheep cell
agglutination test."2 Tests for this factor not only permitted
accurate diagnosis of RA, but also taught us how joints are attacked in
RA. What came to be called "rheumatoid factor" turned out to
be yet another autoantibody, of great size and with a tendency to form
sludge in the blood. Normal human antibodies, the "self" in
this case, were recognized as "non-self" by rheumatoid factor.
The agglutination reaction in a test tube was a pretty good reflection
of what happens in life. In patients with RA, complexes of antibodies
containing rheumatoid factor form in the blood like iles flottant; they
become trapped in joint spaces, joint cells try to get rid of the
unwanted debris, cry havoc, and let loose the dogs of inflammation:
anaphylatoxins C3a, C5a, and eicosanoids, etc. As with Hargraves and the
LE cell, the discovery of rheumatoid factor made it possible to make
sense of yet one more of our diseases. Another finding, RA is an immune
complex disease in which complement is activated, as Peter Ward and
Nathan Zvaifler were the first to document. (3)

On April 20, 1949, William A. Laurence of The New York Times broke
news of another discovery announced at a staff meeting at the Mayo
Clinic: "Preliminary tests during the last seven months at the Mayo
Clinic with a hormone from the skin of the adrenal glands has opened up
an entirely new approach to the treatment of rheumatoid arthritis, the
most painful form of arthritis, that cripples millions, it was revealed
here tonight." (4)

That evening, Philip Hench, Charles Slocumb, and Howard Polley had
reported their experience with 14 cases of RA treated with a precious
material called "Kendall's compound E," or 17 hydroxy-11
dehydro-corticosterone. (5) Cortisone had entered the clinic.

Within a week, cinemas nationwide showed newsreels of cripples
rising miraculously from their wheelchairs. By May of 1949, Hench and
coworkers reported the "complete remission of acute signs and
symptoms of rheumatoid inflammation" at the Association of American
Physicians in Atlantic City. In June, they added success with rheumatic
fever to the cortisone legend at the Seventh International Congress of
Rheumatic Diseases in New York. Many will never forget the waves of
applause after Hench's dramatic film clips were shown to a packed
crowd at the Waldorf As toria. One could actually "do"
something about a crippling disease like RA.

<01-TB001>

In October 1950, the Nobel committee announced that Philip Hench
and the two biochemists who had painstakingly isolated and described the
chemistry of adrenal steroids, Thaddeus Reichstein (University of Basel,
Basel, Switzerland) and Edward Kendall (Mayo Clinic, Rochester, New
York, U.S.), would receive the Nobel Prize in Physiology or Medicine for
"their discoveries relating to the hormones of the adrenal cortex,
their structure and biological effects." (6) Hench remains the only
rheumatologist among Nobel laureates. So universal was the acclaim for
cortisone that the Swedish announcement of the 1950 Nobel Prize in
literature (Bertrand Russel) was almost a footnote in the world press.

Studies of how cortisone works its magic in RA and SLE led two
generations of rheumatologists into the field. These studies contributed
both to the basic science of immunology and to the treatment of patients
with rheumatic disease. It must be admitted, however, that nothing we
have learned since Hench's Nobel Prize has given us any notion of
what causes either lupus or RA. We have, however, learned much about how
immune reactions mediate the pathology of RA and SLE.

IgG/IgM complexes have been implicated in RA since the early work
in Joseph Hollander's lab. He explained the crucial experiments of
1965:

When such complexes are taken up by phagocytes in the joint, they
form the "RA cell," a cell analogous to the LE cell of
Hargraves. The circulating complexes are not specific for RA, being
found in other rheumatic and autoimmune diseases, as well as having a
low prevalence in the normal population. Recently, other antigens
resulting in autoimmune complex formation with greater specificity for
RA have been described. These antibodies, known as anti-cyclic
citrullinated peptide (anti-CCP) antibodies, recognize citrullinated
protein residues, which are present as antigenic determinants in
patients with RA.8 Mart Mannik had earlier found that some 7s IgG
rheumatoid factors self-aggregate to form larger immune complexes via
hydrophobic interactions to become trapped within the synovial tissue.
(9)

This "complex-laden" setting is in contrast to that of
SLE, another autoimmune disease characterized by immune complexes in the
systemic circulation. In the case of SLE, 7s IgGs directed against
several nuclear antigens localize mainly in the kidneys and blood
vessels. (10) They also produce cerebral and pulmonary disease by
activating complement systemically. (11) Genetic defects in the
complement cascade associated with SLE result in inadequate clearance of
immune complexes, as well as apoptotic blebs containing autoantigens.
(12)

Table 1 summarizes the role of immune complexes in the two
diseases. In RA, immune complexes cause local joint inflammation by
activating complement but also stimulate phagocytes directly.
Neutrophils, which comprise more than 90% of the total cell population
in synovial fluid, take-up immune complexes via Fc receptors that
trigger release of hydrolytic enzymes, the generation of reactive oxygen
species, and products of arachidonic acid metabolism. These promote an
inflammatory response or lead directly to tissue degradation, or both.
(13)

We could say, therefore, that tissue injury in RA is due to a
combination of phagocytosis (innate immunity) and anaphylaxis (acquired
immunity) gone awry. Immune complexes create their havoc via Fc gamma
III receptors that signal via the tyrosine phosphorylation
immunoreceptor pathway. Anaphylatoxins, mainly C5a, signal via the MEK/
MAP kinase cascade, and both engage in cross-talk via NF kappa B. We now
appreciate that cytokines, such as TNF alpha and IL-1, are important
mediators of inflammation in RA, (14) but in the joint they act
downstream of the primary insults: immune complexes and anaphylatoxins.
Many of the currently used and developing therapeutic strategies against
RA are successfully targeted toward these cytokines, first appreciated
as "lymphokines." (15) Others are directed toward the
cell-cell interactions between subsets of T cells and B cells--and now
of other antigen-presenting cells--that produce the auto-antibodies in
the first place.

Although we have no clue as to the true etiology of either SLE or
RA, we have dramatically changed the treatment of both diseases. The new
biological agents and small molecules that curb rheumatic disease have
resulted from decades of basic discovery made in the lab. We owe much to
the pioneers of experimental rheumatology who have taught us the basic
facts outlined herein: K. Frank Austen, Claude Bennett, Charles
Christian, Frank Dixon, Edward C. Franklin, Joseph Hollander, Halsted
Holman, Stephen Krane, Henry Kunkel, Mart Mannik, Hans Mueller-Eberhart,
Lewis Thomas, John Vaughan, Morris Ziff, and Nathan Zvaifler.

Disclosure Statement

The author has no financial or proprietary interest in the subject
matter or materials discussed, including, but not limited to,
employment, consultancies, stock ownership, honoraria, and paid expert
testimony.

Gerald Weissmann, M.D., is Director of the Biotechnology Study
Center, New York University School of Medicine; Research Professor,
Division of Rheumatology; and Professor Emeritus of Medicine, Department
of Medicine, NYU Langone Medical Center, New York, New York.

To test further our hypothesis of the immunopathogenesis of
rheumatoid arthritis, we isolated gamma-G from rheumatoid serum and
injected a few milligrams of this into an uninflamed knee joint of
the patient from whom the serum was obtained. In every case, an
acute joint inflammation developed within hours, but gamma-G from
normal donors, prepared identically and in the same dose, caused no
reaction in the contralateral knee at the same time. Rheumatoid
gamma-G injected into osteoarthritic joints (seronegative for
rheumatoid factor) produced no inflammatory response. (7)